Acromegaly is a disease caused by excessive secretion of GH from pituitary adenomas. The estimated world-wide market for SOMAVERT® (pegvisomant, a human GHR antagonist) is over 160 M USD. SOMAVERT® is administered to patients who have failed pituitary adenoma surgery and are resistant to somatostatin analogs [1]. A major downside to SOMAVERT® treatment is that it is administered as a once daily injection (Pfizer). Thus a GHR blocker such as that being proposed here, that can block hGHR signaling would be very desirable in the treatment of acromegaly.
Age is a major risk factor for many types of tumors resulting in a markedly increased cancer incidence in the elderly population [2-4]. Most cancers (78%) are diagnosed in persons 55 years of age and older (source: American Cancer Society). Age is also associated with increased chemotherapy toxicity, which limits the safety and efficacy of standard chemotherapy [5-7]. In clinical reports, elderly patients experienced more myelosuppression and had a greater risk of chemotherapy-related death than younger patients in many types of cancers [6]. This poses a serious problem considering that most cancers occur in elderly individuals who are also more susceptible to chemotherapy toxicity. Although new and less toxic drugs are slowly replacing or being added to the widely used toxic chemotherapy drugs, interventions to reduce toxicity in the elderly are not established [8]. As underlined recently in Nature Reviews in Clinical Oncology in an article titled “Reducing the toxicity of cancer therapy: recognizing needs, taking action”, development of novel strategies and drugs aimed at selective host/patient protection could reduce the side effects associated with chemotherapy treatment and also increase the therapeutic index. Because these drugs would protect against both exogenous and endogenous toxins, they would also have the potential to protect against age-related damage and diseases including cancer, diabetes and neurodegenerative diseases.
It is estimated that by 2030 roughly 20% of the American population will be comprised of individuals 65 and older (source: cdc.gov). Chronic diseases such as heart disease, cancer, Alzheimer's disease and diabetes are the most frequent causes of mortality in the elderly. About 95% of health care costs among older adults (65 and older) go towards chronic diseases and these costs are expected to increase by 25% by 2030 (CDC.gov). Thus, there is a great emphasis on preventing and/or delaying chronic health conditions in the aging population not only to improve quality of life in the elderly but also to curtail rising health care costs.
The basis for targeting the growth hormone receptor (GHR) is as follows. Mutations that cause genetic inhibition of the GH/GHR/IGF-1 lead to as much as a 50% increase in life span in mice [9-11]. Homozygous Ames dwarf mutations in the Prop-1 gene (df/df) prevent the generation of the anterior pituitary cells that produce growth hormone, thyroid stimulating hormone, and prolactin. Young adult df/df mice are approximately one third of the size of control mice but survive >50% longer [9]. This effect of dwarf mutations on life span appears to be caused by the absence of plasma GH, which stimulates the secretion of IGF-1 from liver cells [12]. In fact, IGF-1 is reduced dramatically in the plasma of df/df mice. The plasma GH deficiency appears to mediate the effects of Prop-1 (Ames dwarf) and Pit-1 (Snell dwarf) mutations on longevity, since the mice that cannot release GH in response to growth hormone releasing hormone (GHRH) also live longer [12]. Furthermore, dwarf mice with high plasma GH, but a 90% lower circulating IGF-1 (growth hormone receptor/GH binding protein knock mice, GHRKO) live longer than their wild type littermates [10]. Taken together these studies suggest that the reduction in plasma IGF-1 and probably insulin is responsible for a significant portion of the life span increase in dwarf, GH deficient, and GHR/BP null mice. In fact, mice lacking one copy of IGF-1 receptor (IGF-IR+/−) live 33% longer than their wild type controls [11]. As observed in long-lived lower eukaryotes, the activities of antioxidant enzymes superoxide dismutases and catalase are decreased in murine hepatocytes exposed to GH or IGF-1 and in transgenic mice overexpressing GH [13, 14]. In vitro studies with fibroblasts from mutant mice with deficiencies in the GH/IGF-1 axis show increased resistance against various types of stress including UV, H2O2, paraquat, alkylating agent, heat, and cadmium [15]. In rats, IGF-1 attenuates cellular stress response and the expression of stress response proteins HSP72 and hemeoxygenase [16]. Studies by Longo and colleagues in primary neurons suggest that IGF-1 sensitizes cells to oxidative stress by a Ras/Erk-dependent mechanisms [17]. The Longo laboratory and others have described how mutations that decrease the activity of the Tor/Sch9 (homolog to mammalian AKT and S6K) pathway or of the adenylyl cyclase/cAMP/PKA pathway increase life span and stress resistance in yeast [18-20]. The increase in resistance to oxidants and heat, for example, can reach 1,000 fold in yeast with mutations in both pathways [21].
Recently, a reduction in adenylyl cyclase activity by deletion of the adenylyl cyclase 5 (AC5) gene was also shown to extend life span and increase resistance to oxidative stress in mice [22], suggesting that pathways including homologs of Akt, S6 kinase and cAMP/PKA may play a partially conserved role in the regulation of aging and stress resistance in organisms ranging from yeast to mice (FIG. 2) [23]. Analogous to the activation of yeast Sch9 and Ras by glucose, the mammalian IGF-1 receptor activates both Akt/mTOR/S6K and Ras, and regulates glucose metabolism and cellular proliferation [24]. Accumulating evidence has implicated increased IGF-1 or IGF-1 signaling as risk factors in a variety of cancers [25], suggesting that this pro-mitotic pathway can promote aging and also the damages and mutations necessary for tumorigenesis.
More recently a study of 99 living and 53 deceased Ecuadorian individuals with genetic inhibition of the GHR (Growth Hormone Receptor Deficient, GHRD) has shown that absence of GH/IGF-1 signaling protects against two major age-related diseases, cancer and diabetes [26]. GHRD individuals, who have very low IGF-1 levels appear to have a normal life span that is similar to their non-GHRD counterparts [26]. Thus inhibition of GH/IGF-1 signaling by drug interventions has the potential to be useful in reducing the incidence of cancer and diabetes particularly in families with a high incidence of these diseases. As discussed earlier, inhibition of GH/IGF-1 signaling would have many other applications: chronic treatment of acromegaly (excessive GH production) [27], differential protection against chemotoxicity [28], and oxidative stress associated with ischemia/reperfusion-induced damages [29].
The inhibition of GHR-IGF-1 signaling has also recently been shown to promote hematopoietic regeneration (Cheng et al., Cell Stem Cell 2014) and stem cell based regeneration of multiple systems (U.S. Pat. Appl. No. 20140227373). Moreover, the genetic inhibition of the GHR protects mice from chemotherapy-induced immune suppression (FIG. 3A) and DNA damage in bone marrow and mononuclear peripheral blood cells, in part by causing hematopoietic stem-cell dependent regeneration (FIG. 3B) (Cheng et al., Cell Stem Cell 2014). It has also been demonstrated that the genetic inhibition of the GHR reduces tumor growth and enhances the survival in a xenograft tumor model in mice (FIG. 4). Finally, Parrella et al. have recently shown that inhibition of GH-IGF-1 signaling protects from the age-dependent cognitive impairment and pathology in an Alzheimer's disease mouse model (Parrella et al., Aging Cell. 2013 April; 12(2) 257-68).
Accordingly, there is a need for developing new disease treatment protocols based on the inhibition of GHR-IGF-1 signaling.